Abstract Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of normal muscle atonia during REM sleep and dream enactment behaviors. Individuals diagnosed with RBD have over 90% risk of developing ?-synuclein-specific neurodegeneration. RBD therefore reflects a pre- manifest stage of synucleinopathies, and an opportunity to improve our understanding of these disorders. Dopaminergic dysfunction and neuronal degeneration of several brainstem regions, likely responsible for the emergence of RBD prior to cardinal features of synucleinopathies, destabilize the ?on-off-switch? pattern of regulation of the sleep-wake cycle. The ?on-off-switch? for overall sleep-wake regulation, objective sleepiness and subjective alertness, and REM sleep itself are all strongly influenced by the endogenous circadian system. Our pilot studies in patients with RBD, and in de novo and advanced Parkinson's disease (PD), the most common synucleinopathy, reveal: (i) blunting of the circadian rhythm of melatonin, a well established marker of circadian rhythms; (ii) decreased melatonin amplitude in PD patients with excessive daytime sleepiness compared to those without; (iii) impaired circadian expression of circadian clock genes in PD patients with excessive sleepiness and poor sleep; (iv) loss of clock-dependent markers of REM sleep in RBD; and (iv) beneficial effects of light therapy, a major circadian-based intervention, on sleep and alertness in PD patients. These observations provide the rationale to study the circadian system in RBD. The hypothesis is that circadian disruption causing decreased amplitude (i.e., strength) of circadian rhythmicity plays an important role in pathogenesis of RBD. Indeed, exogenous melatonin lessens RBD symptoms. In our proposed work, the circadian rhythms of 15 RBD patients and 15 age- and gender-matched controls will be studied under well-controlled circadian experimental conditions. Specific Aim 1 will examine the strength of the circadian signal, through the assessment of the amplitude of melatonin concentrations, and objective daytime sleepiness. Specific Aim 2 will quantify circadian clock-dependent REM sleep characteristics including the duration of each REM period, REMs index (i.e., REM frequency) and electromyographic activity during REM sleep across the night. Participants will have inpatient assessments for melatonin, alertness and sleep using polysomnography. Successful completion of the research will both provide additional insight into the pathophysiology of RBD, and inform future studies of the circadian system as a novel diagnostic and therapeutic target for ?-synuclein specific neurodegenerative disorders, including PD. This project is responsive to several highest priority areas for clinical research in the most recent NINDS PD Research Consensus Meeting and in the NIH Sleep Disorders Research Plan: (i) develop effective treatments for non- motor features of PD; (ii) advance the understanding of sleep and circadian functions in both the brain and body; and (iii) improve prevention, diagnosis, and treatment of sleep and circadian disorders.